The liver, the major drug eliminating organ, plays an important role in the disposition of drugs and metabolites. The importance is further emphasized in oral therapy when a significant portion of the dose is reduced by the liver before a drug reaches the systemic circulation, a phenomenon known as the first-pass effect. The fate of a metabolite may also be determined by the liver when it serves as a substrate for hepatic removal either at the time of its genesis or upon recirculation as the preformed metabolite. An understanding of the manner in which hepatic clearances of drugs and metabolites proceed becomes mandatory if the safety and efficacy of drugs are to be safeguarded, especially when the drug and/or its metabolites are pharmacologically active or toxic. We believe that hepatic clearances of drugs and of metabolites can be better understood, categorized, and ultimately predicted on the basis of the rapidity with which drug molecules reach the sites of elimination with respect to the delivery of drug via blood flow. We propose to study the effects of liver blood flow on the clearance of two highly extracted compounds, ethanol and meperidine, which are of opposite polarity, in the perfused rat liver in situ preparation. We also propose to study the elimination kinetics of two drug-metabolite pairs, 14C-lidocaine-MEGX, and phenacetin-d8, phenacetin-d0-3H-acetaminophen during normal and retrograde perfusions in the same system to investigate the effects of the direction of blood flow on the elimination kinetics of a metabolite formed from its precursor and of the preformed metabolite. Drug detection and quantitation will be performed by gas chromatography, high pressure liquid chromatography, and mass spectroscopy. These results may elucidate the possible existence of zonal distribution of enzyme systems within the liver, and define the role of drug diffusivity in the liver, in addition to other physiological determinants, namely organ blood flow, drug binding, and the hepatic intrinsic clearance on the hepatic clearances of drugs and of their metabolites.